Piperidine carboxamides and derivatives thereof



United States Patent 3,133,061 PIPERIDINE CARBOXAMIIDES AND DERIVATIVES THEREOF Frederick K. Kirchner, Bethlehem, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Nov. 13, 1962, Ser. No. 237,320 30 Claims. (Cl. 260247.1)

This invention relates to substituted piperidines.

The invention herein claimed resides in the concept of compositions of matter having a molecular structure in which a carbamyl, substituted-carbamyl, thiocarbamyl or substituted-thiocarbamyl group is attached to the nitrogen atom of the piperidine ring of substituted-aminoalkylpiperidines. There is also disclosed processes for physically embodying such concept and the utility inherent in the embodiments so produced.

The substituted-aminoalkylpiperidine moiety of the 1-carbamyl-, 1 substituted carbarnyl-, thiocarbamylor l-substituted-thiocarbarnyl substituted aminoalkylpiperidines of the invention is not limited as to type or number of substituents, and for operativeness need only carry a hydrogen on the piperidine ring nitrogen prior to conversion to the appropriate 1- carbamyl-, 1- substituted-carbarnyl-, thiocarbamylor 1 substituted thiocarbamylpiperidines.

Such compounds contain the nucleus represented by the structural formula which carries a substituent secondary or tertiary-aminoalkyl group and which may in addition carry other substituents or combinations of substituents on the nucleus in any of the positions not occupied by the substituent secondary or tertiary-aminoalkyl group.

The compounds of the invention can therefore be represented in the broad sense by the generalized formula Y- AZ wherein Y represents a l-carbamyl-, l-substituted-carbamyl-, thiocarbamylor l-substituted-thiocarbamylpiperidyl moiety, A represents an alkyle'ne group having from one to about six carbon atoms and Z reprevIn .the above general formulas, Q represents the rewherein Z represents a member of the group consisting of 3,133,061 Patented May 12, 1964 maining portion of the piperidine moiety and Hal is a halogen atom.

The reaction depicted in Equation 1 is conveniently carried out at a temperature between about 35 C. and C. in the presence of sufiicient acid to liberate cyanic acid. Although the reaction can be carried out at room temperature and in an inert solvent, as for example, benzene, toluene, chloroform and the like, it is preferred to carry out the reaction by heating the reactants in a nonmineral acid, as for example acetic acid. In this case the acetic acid also acts as a solvent for carrying out the reaction. About equimolar amounts of the reactants are used although the amount of alkali metal cyanate can be varied up to about two molar equivalents per molar equivalent of amine.

Alternatively the preparation of the l-carbamyl compounds can be carried out by heating the amine with urea at a temperature between C. and 160 C., preferably about C. The reaction mixture is heated from three to nine hours and the desired compounds recovered by distillation or crystallization.

The reaction shown in Equation 2 above is carried out in a dry solvent as, for example, benzene, toluene or the like, in the presence of an acid-acceptor such as sodium bicarbonate. The reaction takes place at about room temperature and is generally complete in about one hour and the desired products recovered by distillation.

The preparation of the l-substituted-carbamyl or 1- substituted-thiocarbamylpiperidines according to Equations 3 and 4 above is preferably carried out in a solvent inert under the conditions and to the reagents used in carrying out the reaction and includes lower-alkanols, ethanol, etc. in the case of (3) and benzene, toluene, etc. inthe case of (4). The reaction can be carried out by merely mixing the reactants at room temperature. However, it is more practical to carry out the reaction in an inert solvent at a temperature between 50 C. and 75 C., in which case the reaction is usually complete in ten to fifteen minutes. The desired products are recovered by filtration and recrystallization.

A preferred group of compounds comprises those having the structural formula monocarbocyclic arylamino, dialkylamino and alkylcneamino and nitrogen or oxygen or sulfur-interrupted alkyleneamino groups, thealkylene portions ofwhich contain four totwelve carbon atoms and which, with the amino nitrogen, form a ring containing four to six carbon atoms, A represents an alkylene radical having from one to'about six carbon atoms, X represents a member of the group consisting of oxygen and sulfur, R represents a member of the group consisting of hydrogen, lower-alkyl and lower-alkenyl radicals,-and R. represents a member of the group consisting of hydrogen, lower-alkyl, loWer-alkenyl, phenyl, benzyl and phenyl and benzyl ring substituted by from one to three members of the group consisting of.

. lower-alkyl, lower-alkoxy, nitro, halogen, and trifluoromethyl and W represents a member of the ing of hydrogen and lower-alkyl.

The symbol Z, when representing a monocarbocyclic arylamino group, stands for unsubstituted anilino or anilino substituted by one or more ;substituents inert to the group consist- I tain four to twelve carbon atoms and which with the amino nitrogen form a ring containing four to six carbon atoms, it stands for groups such as l-pyrrolidyl, l-piperidyl, 2,S-dimethyl l-pyrrolidyl, l-hexamethyleniminyl, ethyl-l-piperidyl, 4-butyl-2-methyl-l-piperidyl etc. for alkyleneamino and 4-morpholinyl, 2,6-diethyl-4-morpholinyl, l-piperazinyl, 4-ethyl-l-piperazinyl, 4-pheny1-1-piperazinyl, 4-thiomorpholinyl, 3-thiazolidinyl, 3 hexahydrothiazepinyl, 3-azabicyclo[3.2.2]nonane and the like for interrupted alkyleneamino groups.

The A in the above Formula I represents a divalent alkylene radical having from one to about six carbon atoms and hence includes for example, -methylene,

When R and R in the above Formula 1 represent a lower-alkyl or lower-alkenyl group they stand, in the case of lower-alkyl, for groups having from one to about six carbon atoms and thus including for example, radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, isohexyl etc., and when lower-alkenyl for groups such as allyl, l-butenyl, 2-butenyl, l-pentenyl, 3-pentenyl, l-hexenyl and the like.

When R in the above Formula I represents phenyl or benzyl substituted by from one to three substituents selected from lower-alkyl, lower-alkoxy, nitro, halogen and trifiuorornethyl groups, the lower-alkyl and lower-alkoxy groups have from one to about six carbon atoms, thus including such radicals as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isohexyl etc. for lower-alkyl and methoxy, ethoxy, propoxy, butoxy, isobutox-y, pentoxy,

l-hexamethyleniminyl, 2-( 1,2,3,4-tetrahydroisoquinolyl 4-phenyl-1-piperazinyl, 4-lower-alkyl-l-piperazinyl, 4-(2- hydroxyethyl)-1-piperazinyl, anilino and anilino substituted by from one to three members of the group consisting of lower-alkyl and lower-alkoxy groups.

A particularly preferred aspect of the invention relates to compounds having the formulas III and I X C wherein X, R, R and T have the meanings given above because of the ease of preparation and ready availability of the intermediates as will be seen hereinafter.

In the above general Formulas III and 1V, when T stands for lowenalkylated-l-pyrrolidyl, l-piperidyLA-morpholinyl or 4-loWer-alkyl-l-piperazinyl groups it represents such rings substituted at any of the available p0sitions by one to two lower-alkyl groups having from one to about six carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, heXy-l and the like.

, ized hitherto. The intermediates are prepared by hydroisopentoxy, hexoxy, isohexoxy and the like .for loweralkoxy and the halogen substituent can be any of the wherein A, W, X, R and R have the meanings given above and T is a member of the group consisting of dilower-alkylamino, l-pyrrolidyl, lower-alkylated l-pyr rolidyl, l-piperidyl, loweralkylated-Lpiperidyl, 4-morpholinyl, lower-alkylated-4-morpholinyl, 4-thiomorpholinyl,

genation of the reaction product resulting-from the condensation of 2- and 4-vinylpyridines with amines.

The substituted-aminoalkylpyridines used in the preparation of the substituted-aminoalkylpiperidines are likewise a known class of compounds certain subgenera and individual members of which have hitherto not been dis closed or characterized. Ihese 2-[2-(4-phenyl-1-piper-' azinyDethyHpyridines are disclosed and claimed in my copending application Serial No. 237,321 filed. November g The intermediates for the preparation of the compounds of Formulas HI and IV as well as those represented by Formula I can be. prepared by a'number of methods known to those skilled in the art. Thus, the condensation of 2- or 4-n1ethylpyridines with substituted-amino alkyl halides in the presence of sodamide followed by 7 reduction of. the pyridine ring leads to compounds wherein the alkylene bridge is varied:

Alternatively, the amides resulting from the condensation of w-pyridylalkanoic acid esters with amines or the ketones from the Clais'en condensation between py'ridylcarboxylic acidesters and w-substituted-arninoalkanoic acid esters can be reduced with, for example, lithium aluminum hydride according to the following illustrative equations:

As a specific example, the application of the above syntheses to the preparation of 3-[3-(1-pyrrolidyl)propyl] piperidine is given below:

] COOCzH5 C2H5OOCCH2OH2N The acid-addition salts and the quaternary ammonium doses of the-salts, so that the beneficial physiological prop-.

erties inherent in the free bases 'are not vitiated by side effects ascribab-le to the anions; in other words, the latter do not substantially increase the toxicity inherent in the cations. Appropriate acid-addition salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid, and phosphoric acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, ethanesulfonic acid, and quinic acid. The quaternary ammonium salts are obtained by the addition of esters of strong acids to the free base form of the compounds, said esters having a molecular weight less than about 200. 'A preferred class of esters comprises alkyl, alkenyl, and monocarbocyclic 'aryl-lower-alkyl esters of strong inorganic acids or organic sulfonic acids, including such compounds as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, allyl chloride, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluenesul fonate, benzyl chloride, benzyl bromide, and substituted benzyl halides, such as p-chlorobenzyl chloride, p-nitrobenzyl chloride, p methoxybenzyl chloride, o-chlorobenzyl chloride, and the like. i

The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid, and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

-The quaternary ammonium salts are prepared by mixing the free base and ester of a strong acid in an inert solvent. lHeating may be used to facilitate the reaction, although salt formation usually takes place readily at room temperature. The quaternary ammonium salt separates directly or can be obtained by concentration of the solution.

It is also possible to convert one quaternary ammonium salt to another in which the anion is different. If the anion of the original quaternary salt forms a waterinsoluble silver salt, the quaternary salt will react with silver oxide in aqueous medium to form the corresponding quaternary annnonium hydroxide, the original anion being removed as a precipitate. The quaternary am.- monium hydroxide solution can then be neutralized with any'desired acid, weak or strong, to produce a new quaternary ammonium salt in which the anion is different from that of the original salt. In this Way quaternary ammonium salts in which the anion is derived from a weak acid can be obtained. 7

Although therapeutically acceptable salts are preferred, those having toxic anions are also' useful when employed as intermediates in the purification of the free base and in conversion to 'other salts, and as characterizing derivatives of the free bases.

Thus it will be appreciated the acid moieties or anions which can be associated in the salt forms are in themselves'neither novel nor critical and therefore can be any glacial acetic acid was hydrogenated over Adams .catalyst v at room temperature for a period of six and o'ne half hours. The catalyst was removed by filtratiQn andYthe solution made basic with 35% sodiumhydroxider The oil which separated was taken up in benzene and the hen:- zene extract 'dried over-anhydrous calcium sulfate. Addition of ethereal hydrochloric acid caused the separation of a gum-like dihydrochloride whichwas boiled in anhydrous ethanol after the benzene was decanted. Theresultant white solid was recrystallized from anhydrous 6th? anol to give 73g. of 2-(2-anilinoethyl)piperidine dihydr'ochloride, MLP. 219-222 C. (corn).

Analysis;-Calcd. Or c gHggclzNgi N, Ci, 25.57- Found: N, 10.09; Cl. 25.40. I

The above dihydrochloride was dissolved in water and the solution made basic with ammonium hydroxide. The oily crystals which precipitated were dissolved in benzene, the benzene solution concentrated then triturated with n-pentane. After the white solid which separated was recrystallized several times from an ethanol-water mixture there was obtained 2-(Z-anilinoethyl)piperidine, MP. 50- 52 C. (corr.).

Analysis.Calcd. for C H N C, 76.42; H, 9.87; N, 13.71. Found: C, 76.37; H, 10.14; N, 13.86.

(b) 1-carbamyl-2-(2-anilinoethyl)piperidine: A mixture of 5.1 g. of 2-(2-anilinoethyl)piperidine and 2.25 g. of potassium cyanate in 25 cc. of glacial acetic acid was heated for one hour on a steam bath. The solution was poured into 200 cc. of water and the resultant solution made basic with sodium hydroxide. The mixture was extracted four times with chloroform and the chloroform extracts dried over calcium sulfate. After removal of the chloroform by distillation under diminished pressure, the residual gum was taken up in benzene and left standing for forty-eight hours. The solid which separated was collected by suction filtration and dried and there was thus obtained 2.4 g. of 1-carbamy1-2-(2-anilinoethyl)piperidine, M.P. 120-127 C. (corn).

Analysis.Calcd. for C H N O: C, 67.98; H, 8.56; N, 16.99. Found: C, 67.89;H, 8.65; N, 16.73.

The minimum effective hypotensive dose (MEHD) of l-carbamyl-Z-(2-anilinoethyl)piperidine given subcutaneously in the renal hypertensive rat was found to be 0.01 mg./kg. The hypotensive effect lasted for forty-eight hours and the maximum drop in blood pressure was reached in two hours.

Example 2 (a) 2-[2-(l-pyrrolidyl)ethyl]piperidine was prepared by the hydrogenation of 264 g. of 2-[2-(l-pyrrolidyl) ethyl] pyridine in 750 cc. of glacial acetic acid using the manipulative procedure described above in Example 1(a). The oil which separated was distilled under vacuum to give 186 g. of 2-[2-(l-pyrrolidyl)ethyllpiperidine, B.P. 80.0 C./0.2 mm.

Analysis.Calcd. for C H N C, 72.87; H, 12.17; N, 15.37. Found: C, 72.36; H, 12.09 N, 15.16.

(b) l-carbamyl 2 -[2-(l-pyrrolidyl)ethyl]piperidine was prepared from 21.9 g. of 2-[2-(1-pyrrolidyl)ethyl] piperidine and 9.75 g. of potassium cyanate in 75 cc. of

glacial acetic acid using the procedure described above in Example 1(b). After recrystallization from n-hexane there was obtained 8.9 g. of 1-carbamyl-2-[2-(1-pyrro1- idyl)ethyl]piperidine, M.P. 107109 C. (corn).

Analysis.-Calcd. for C H N O: C, 63.96; H, 10.29; N, 18.65. Found: C, 64.26; H, 10.28; N, 18.40.

(c) l-carbamyl 2 [2'-(l-pyrrolidyl)ethyllpiperidine methiodide was prepared by refluxing 11.25 g. of l-carbamyl-2-[2-(1-pyrrolidyl)ethyl]piperidine with g. of methyl iodide in 100 ml. of methanol for two hours. Trituration of the reaction mixture with ether gave 12.5 g. of 1-carbamyl-2-[2-(l-pyrrolidyl)ethyl[piperidine, M.P. 170-171 C. (corn).

Analysis.Calcd. for C H IN O: I, 34.56; N, 11.44. Found: I, 35.06; N, 11.23.

(d) l-carbamyl 2 [2-(l-pyrrolidyDethyl]piperidine methyl p-toluenesulfonate was prepared by mixing 5.63 g. of l-carbamyl 2 [2-(l-pyrrolidyl)ethyl]piperidine with 4.65 g. of methyl p-toluenesulfonate in 50 ml. of dry benzene and allowing the mixture to stand overnight at room temperature. The benzene was removed by heating on a steam bath and the residue taken in absolute ethanol. Trituration with anhydrous ether gave. a finely divided solid which was collected by filtration. After drying overnight in a vacuum desiccator there was obtained 5.62 g. of l-carbamyl-Z-[2 (1-pyrrolidy1)ethyl]piperidine methyl p-toluenesulfonate, M.P. 160-162 C. (corn).

idine produced an average fall in both systolic and diastolic blood pressure of fifteen percent below the control in trained unanesthetized normotensive dogs at a dose of 1.0 mg./ kg. intravenously. There was no alternation of the heart rate of the dogs nor were there any indications of side effects such as sedation, diarrhea or panting. Acute intravenous toxicity determinations in mice and dogs indicate that l-carbamyl-2-[2-(l-pyrrolidyDethyl] piperidine has ALD s of 160:130 mgjkg. and 50, 200 mg./kg. respectively (approximate lethal dose in 50% of the animals). Acute oral toxicity determinations in mice indicate that the LD is 3000 trig/kg.

Example 3 (a) 4-(2-anilinoethyl)piperidine: A mixture of 30 g.

of 4-(2-anilinoethyl)pyridine and 750 cc. of anhydrous ethanol was heated to reflux then treated with 100 g. of sodium, added over one hour. The mixture was refluxed for one hour then the solution was decanted from a black solid which separated. Water was added to the supernatant to cause the separation of two phases which were extracted with benzene. The benzene extracts were dried over anhydrous sodium sulfate and the benzene removed by distillation under diminished pressure. The brown residue which remained was recrystallized several times from n-hexane to give 11.2 g. of 4-(2-anilinoethyl)piperidine, M.P. 92-94 C. (corn).

Analysis.-Calcd. for C H N C, 76.42; H, 9.87; N, 13.71. Found: C, 76.22; H, 9.53; N, 13.75.

(b) l-carbamyl 2 (Z-anilinoethyl)piperidine can be prepared by heating 4-(2-anilinoethyl)piperidine with potassium cyanate using the manipulative procedure described above in Example 1(b).

Example 4 p (a) 2-[2-( l,2,3,4 tetrahydroisoquinolyl-Z)ethyllpyridine: To a solution of 100 g. of 1,2,3,4-tetrahydroisoquinv oline in 400 cc. of dry methanol and 43 cc. of glacial acetic acid was added while heating and stirring 78.8 g. of 2-vinylpyridine. When the addition was complete heating and stirring was continued for five hours. The

solution was concentrated by evaporation and the residue poured onto ice and the. aqueous mixture made basic with sodium hydroxide. dried and distilled to give 103 g. of 2-[2-(1,2,3,4-tetrahydroisoquinOlyl-Z)ethyl]pyridine, B.P. 150-153" C./ 0.28

11.76. Found: C, 80.91; H, 7.85; N, 11.69.

(b) 2-[2-(1,2,3,4 tetrahydoisoquinolyl-2) ethyl] piperidine was prepared by hydrogenation of 95.3 g. of2-[2- (1,2,3,4-tetrahydroisoquinolyl-2)ethyl] pyridine in 300 cc.

' of glacial acetic acid using the manipulative procedure described above in Example 1(a).

The oil which separated was Analysis-Called. for C H N z c, 80.63; H, 7.61; N, V

lowing the manipulative procedure described above in EX- ample 1(b). The white solid remaining afte the basic solution was extracted with ether was taken up in chloroform and n-pentane added. After standing overnight at room temperature white crystals separated. The crystals were removed by filtration, recrystallized from a chloroform-n-pentane mixture and dried. There was thus obtained 8.8 g. of l-carbamyl-2-[2-(l,2,3,4-tetrahydroisoquinolyl-2)ethyl]piperidine, M.P. 126-129" C. (corr.).

Analysis.--Calcd. for C17H25N3OZ C, 71.04; H, 8.77; N, 14.62.- Found: C, 71.27; H, 8.81; N, 14.44.

The MEHD of 1-carbarnyl-2-[2-(1,2,3,4-tetrahydroisoquinolyl-2)ethyl]piperidine given subcutaneously in the renal hypertensive rat was found to be 0.10 mg./kg. The acute intravenous toxicity in the mouse was found tobe 60 mg./kg.

Example 5 1-carbamyl2-[2-(l-piperidyl)ethyl]piperidine was prepared from 19.5 g. of 2-[2-(l-piperidyl)ethyl]piperidine and 8.2 g. of potassium cyanate in 75 cc. of glacial acetic acid using the manipulative procedure described above in Example 1(b). The liquid remaining after removal of the chloroform solidified on standing and the solid thus obtained was collected by filtration. The white solid was taken up in hot n-hexane and the solution cooled in an ice bath. The solid which separated was collected and dried to give 6.2 g. of l-carbamyl-2-[2-(l-piperidyl)ethyl]piperidine, M.P. 120-127 C. (corr.).

Analysis.--Calcd. for C H N O: C, 65.23; H, 10.53; N, 17.56. Found: C, 65.46; H, 10.28; N, 17.39.

Example 6 1-carbamyl-4- [2- l-piperidyl) ethyl] piperidine was prepared from 19.5 g. of 4-[2-(l-piperidyl)ethyl]piperidine and 8.2 g. of potassium cyanate in 75 cc. of glacial acetic acid using the manipulative procedure described above in Example 1(b). The residue remaining after removal of the chloroform was taken up in n-pentane and left standing. The solid which separated was collected by filtration, recrystallized from a chloroform-n-pentane mixture, and dried. There was thus obtained 6.6 g. of l-carbamyl- 4 [2 (1 piperidyl)ethyl]piperidine, M.P. 144-l46 C. (corr.).

Analysis.Calcd. for C H N O: C, 65.23; H, 10.53; N, 17.56. Found: C, 65.23; H, 10.60; N, 17.45.

The MEHD of l-carbamyl-4-[2-(l-piperidyl)ethyl]- piperidine given subcutaneously in the renal hypertensive rat was found to be 0.10 mg./kg. The acute intravenous toxicity in the mouse was found to be 170 mg./kg.

Example 7 zation from n-hexane gave 8.9 g. of l-carbamyl-S-ethyl-Z- [2 (1 piperidyl)ethyl1piperidine, M.P. 109-116 C. (corr.).

Analysis.Calcd. for C H N O: C, 67.37; H, 10.93; N, 15.71. Found: C, 67.22; H, 11.17; N, 15.61.

The MEHD of 1-carbamyl-5-ethyl-2-[2-(1-piperidyl)- ethyl] piperidine given subcutaneously in the renal hypertensive rat was found to be 0.10 mg./kg. The acute intravenous toxicity in the mouse was found to be .mgJkg.

Example 8 l-carbamyl 4 [2-(l-pyrrolyidyl) ethyl]piperidine was prepared from 18.1 g. of 4-[2-(l-pyrrolidyl)ethyl1p1peridine and 8.2 g. of potassium cyanate in 75 cc. of glacial 10 acetic acid using the manipulative procedure described above in Example 1(b). After recrystallization from a chloroform-n-hexane mixture there was obtained 1.9 g. p

Example 9 (a) 2- [2-(4-phenyl-l-piperazinyl)ethyl]pyridine was prepared from 81 g. of l-phenylpiperazine and 52.5 g. of 2-vinylpyridine in 250 cc. of anhydrous methanol and 28.6 cc. of glacial acetic acid using the procedure described above in Example 4(a). After recrystallization from n-hexane there was obtained 14.2 g. of 2-[2-(4- phenyl-l-piperazinyl)ethyl]pyridine, M.P. 6061 C.

(corr.).

Analysis.Calcd. for C H N C, 76.37; H, 7.92; N, 15.72. Found: C, 76.38; H, 7.75; N, 15.67.

(b 2- [2- (4-phenyl-1-piperazinyl) ethyl] piperidine was prepared by hydrogenation of 169 g. of 2-[2-(4-phenyl-1- piperazinyl)ethyl]pyridine in 450 cc. of glacial acetic acid using the procedure described above in Example 1(a). Recrystallization from n-hexane gave 69 g. of 2-[2-(4- phenyl-l-piperazinyl)ethyl]piperidine, M.P. 5256 C.

(corr.). Analysis.Calcd. for C17H27N3Z N, 15.37. N, 15.11.

(c) l-carbamyl 2 [2-(4-phenyl-1-piperazinyl)ethyl] piperidine was prepared from 19.9 g. of 2-[2-(4-phenyll-piperazinyl)ethyl]piperidine and 11.8 g. of potassium cyanate in 75 cc. of glacial acetic acid using the manipulative procedure described above in Example 1(b). The addition of sodium hydroxide caused the separation of a pink solidwhich was collected by filtration. After two recrystallizations from ethanol there was obtained 9.1 g. of 1-carbamyl-2-[2-(4-phenyl-1-piperazinyl)ethyl]piperidine, M.P. 188-190" C. (corr.).

Analysis.Calcd. for C H N O: C, 68.32; H, 8.92; N, 17.71. Found: C, 68.62;.H, 8.83; N, 17.60. i The MEHD of 1-carbamyl-2-[2-(4-phenyl-1-piperazinyl)ethyl]piperidine given subcutaneously in the renal hypertensive rat was found to be 0.01 mg./kg. The acute intravenous toxicity in the mouse was found to be 60 mg./kg.

Found Example 10 1-carbamyl-2- [2- (4-rnorpholinyl) ethyl] piperidine A mixture of 19.7 g. of 2-[2-(4-morpholinyl)ethyl]piper idine and 3 g. of urea was heated at C. for five hours with stirring. The mixture was cooled to room temperature, n-hexane'added to cause the separation of a white solid. The solid was collected by filtration and recrystallized twice from ethyl acetate. There was thus obtained 9.5 p g. of l-carbamyl-Z-[2-(4-morpholinyl)ethyl] piperidine, M.P. l33 C. (corr.).

Analysis.-Calcd. for C H N O N 17.41; N 5.81. Found: N 18.27; N 5.67.

The MEHD of l-carbamyl-2-[2-(4-morpholinyl)ethyl] piperidine given subcutaneously in the renal hypertensive ratwas found to be 0.01 mg./kg. The acute intravenous toxicity in the mouse was found to be 875 mg./kg.'

Example 11 cedure described above in Example 4(a). After distillation there was thus obtained 120 g. of 4-[2-(1-hexamethylenirninyl)ethyl] pyridine, B.P. 118-121 C./ 0.25 mm.

Analysis.-Calcd. for C H N C, 76.42; H, 9.87; N, 13.71. Found: C, 76.51; H, 10.05; N,13.64.

(b) 4-[2-(1-hexamethyleniminyl)ethyljpiperidine was prepared by hydrogenation of 140.8 g. of 4-[2-(1-hexamethyleniminyl)ethyl]pyridine in 520 cc. of glacial acetic acid using the manipulative procedure described above in Example 1(a). The oil which separated was taken up in ether and the ether extracts dried. Concentration of the solution under reduced pressure followed by distillation of the residual oil gave 114 g. of 4-[2-(1-hexarnethylenirninyl)ethyl]piperidine, B.P. 121-131" C./ 1.0 mm.-

Analysis.Calcd. for C H N C, 74.22; H, 12.46; N, 13.32. Found: C, 75.05; H, 12.24; N, 13.09.

(c) 1 carbamyl 4-[2 (l-hexamethyleniminyl) ethyl] piperidine can be prepared by heating 4-[2-(1-hexamethyleniminyl)ethyl]piperidine with potassium cyanate using the manipualtive procedure described above in Example 1(b).

Example 12 (a) 2- [2- l-hexamethyleniminyl) ethyl] piperidine was prepared by hydrogenation of 107.3 g. of 2-[2-(1-hexamethyleneiminyl)ethylJpyridine in 400 cc. of glacial acetic acid using the manipulative procedure described above in Example 1(a). The oil which separated was taken up in ether and the aqueous layer extracted with additional ether. The combined ether extracts were dried and the ether removed by evaporation under reduced pressure. Distillation of the residual oil gave 34.4 g. of 2-[2-(Lhexamethyleniminyl)ethylJpiperidine, B.P. 103- 105 C./0.8 mm.

Analysis.Calcd. for C H N C, 74.22; H, 12.46; N, 13.32. Found: C, 73.89; H, 12.12; N, 13.26

(b) 1 carbamyl 2-[2-(1-hexarnethyleniminyl)ethyl] piperidine can be prepared by heating 2-[2-(1-hexamethyleniminyl)ethyl]piperidine with potassium cyanate using the manipulative procedure described above in Example 1 b Example 13 1 1 carbamyl 2-[2-(2,6-dimethyl-4-morpholinyl) ethyl] piperidine was prepared from 22.6 g. of 2-[2-(2,6-dimethyl-4-morpholinyl)ethyl]piperidine and 16.2 g. of potassium cyanate in 75 ml. of glacial acetic acid using the manipulative procedure described above in Example 1 (b).

After recrystallization from ethyl acetate there was obtained 4.4 g. of l-carbamyl-Z-[2-(2,6-dimethyl-4-morpholinyl)ethyl]piperidine, M.P. Ill-113 C. (corn).

Analysis.-Calcd. for C14H27N302: C, 62.42; H, 10.10; N, 15.60. Found: C, 62.36; H, 10.01; N, 15.55.

Example 14 Example 15 1-carbamyl2-(Z-diethylaminoethyl)piperidine can be prepared by heating 18.4 g. of 2-(2-diethylaminoethyl)- piperidine with 16.2 g. of potassium cyanate in 75 ml. of glacial acetic acid using the manipulative procedure described above in Example 1(b).

Example 1 6 1 carbamyl 4 2 [2 (2 methoxyanilino)ethyl]pi perid-ine was prepared by heating 23.4 g. of'2-[2-(2- methoxyanilinokthyl]piperidine with 16.2 g. of potas-' sium cyanate in ml. of glacial Metic acid using the manipulative procedure described'above in Example 1(b).

12 The 3 g. of 1-carbamyl-2-[2-(Z-me-thoxyanil-ino)ethylJpiperidine thus obtained had the M1. 148-150 C.

Example 17 1 carbarny 2 (2 dihexylaminoethyhpiperidine can be prepared by heating 29.6 g. of 2-(2-dihexylaminoethyl)piperidine with 16.2 g. of potassium cyanate in 75 of glacial acetic acid using the manipulative procedure described above in Example 1( b).

Example 18 1 carbamyl 4 [2 (4 methyl- '1 piperazinyD- ethyl] piperidine can be prepared by heating 21.1 g. of 2- [4-(4-methyl-1-piperazinyl)ethyl]piperidine with 16.2 g of potassium cyanate in 75 ml. of glacial acetic acid us ing the procedure described above in Example 1(b).

I Example 19 1 carbamyl 2 [2 (2,6 dimethylanilino)ethyl]piperidine can be prepared by heating 23.3 g. of 2-[2,6-dimetl'lylarii-lino)ethyl]piperidine, prepared by hydrogenation of 2-[2-(2,6-dimethylanilino)ethyl]pyridine, with 16.2 g. of potassium cyanate following the procedure described. above in Example 1(b). The 2-[2-(2,6-dirnethylanilino)ethyl1pyridine in turn can be prepared by condensing Z-Vin-ylpyridine with [2,6-dimethylaniline.

Example 20 1 carbamyl 4 [2 (2,5 diethyl 1 pyrrolidyl) ethyl] piperidine can be prepared by the condensation of 4-vinylpyridine with 2,5-diethylpyrrolidine to form 4-[2- (2,5-diethyl-1-pyrrolidyl)ethylJpyridine, reduction to 4- [2-(2,5-dietl1yl-l-pyrrolidyl)ethyl1piperidine and heating of the latter with potassium cyanate.

Example 21 1 carbamyl 4 (2 di n --butylaminoethyl)piperidine hydrobromide can be prepared by heating 4-(2- dim-butylaminoethyl)piperidine with potassium cyanate using the procedure described above in Example 1(b) followed by treatment of the base thus obtained with ethereal hydrogen bromide.

Example 22 1 carbamyl 2 {2 4 isopropylanilino)ethyl]- piperidine ethane sulfonate can be prepared by heating 2- [2-(4-isopropylanilino)ethylJpiperidine with potassium cyanate followed by treatment of the anhydrous 1-.car bamyl-Q-[2-(4-isopropylanilino)ethyl]piperidine with ethane sulfonic acid. The 2-[2-(4-isopropy-lanilino)ethyl] piperidine can be prepared by hydrogenation of 2-[2-(4- isopropylauilino)ethyl]pyridine prepared by condensation of 2-vinylpyridine with 4-isopropylaniline.

Example 23 1 carbamyl 4 [2 (3,4,5 trimethoxyanilino)- ethyl] piperidine can be prepared by the condensation of 4-vinylpyridine with 3,4,5-trimethoxyaniline, hydrogenation to the corresponding 4-[2-(3,4,5-trimethoxyanilino)- ethyllpiperidine and heating of the latter with potassium cyanate.

Example 24 1 carbamyl 2 [2 4 thiomorpholinyl)etl1yl] piperidine can be prepared by the condensation of thiomorpholme with 2-vinylpyridine to form 2-[2-(4-thiomorpholinyl)ethyl] pyridine, reduction to the correspond ing 2-[2-(4-thiomorpholinyl)ethyl]piperidine and heating of the latter with potassium cyanate.

Example 25 1 phenylcarbamyl 2 [1 (pyrrolidyl)ethyl]piperd ne: A solution of 9 g. of 2-[1-(pyrrolidyl)ethyl]piperidine in 50 ml. of dry benzene was treated with 6 g. of phenyl isocyanate and the mixture heated for ten minutes. Dilution of the reaction mixture with n hexane caused the separation of a solid which was collected by suction filtration. There was thus obtained 13.6 g. of 1- phenylcarbamyl 2 [1 (pyrrolidyl)ethyl]piperidine, M.P. 137138 C. (cor-L).

Analysis.Calcd. -for C H N O: C, 61.72; H, 9.03; N, 13.94. Found: C, 71.53; H, 8.78; N, 13.84.

The MEHD of l-phenylcarbamyl-Z-[1 (py11rolidyl) ethyl]piperidine given subcutaneously in the renal hypertensive rat was found to be 0.01 mg./kg.

Example 26 1 phenylthiocarbamyl 2 [2 (1 pyrrolidyl)ethyl]- piperidine: A mixture of 9.1 g. of 2-[2-(1-pyrrolidyl)- ethyl]piperidine and 7 g. of phenylisothiocyanate was refluxed for live minutes. The solid which precipitated was collected by filtration and recrystallized from ethanol to give 13 g. of 1-phenylthiocarbamyl-2-[2-(1-pyrrolidyl)- ethyl]piperidine, M.P. 129-130 C. (corn).

Analysis.CalCd. for C H N S: N, 13.24; S, 10.10. Found: N, 12.98; s, 10.20.

Example 27 1 (4 chlorophenylthiocarbamyl) 2 [2 1 .piperidyl)ethyl]piperidine: To a solution of 9.75 g. of 2- [2-(1-piperidyl)ethyl]piperidine in 50 m1. of absolute ethanol was added 8.5 g. of 4-ch1orophenylisothiocyanate in 30 ml. of absolute ethanol. The solution was warmed on a steam bath for ten minutes then cooled. The white solid which separated was collected and dried. There was thus obtained 14.4 g. of 1-(4-chlorophenylthiocarbamyl) 2 [2 (1 piperidyl)ethyl]piperidine, M.P. 151-154 C. (corn).

Analysis.-Calcd. for C H ClN S: Cl, 9.69; N, 11.48. Found: Cl, 10.03; N, 11.46.

When administered orally to rats infected with the roundworm Strongyloides ram", 1-(4-ch1orophenylthiocarbarnyl) 2 [2 (1 piperidyl)ethyl]piperidine completely cured the animals of the infection at a drug level of 100 mg./kg./day.

Example 28 1 (4 chlorophenylcarbamyl) 2 [2 (1 piperidyl)- ethylJpiperidine was prepared "from 9.75 g. of 2-[2-(1- piperidyl)ethyl]piperidine and 7.66 g. of 4-chlorophenylisocyanate in 50 ml. of dry benzene using the procedure described in Example 25. There was thus obtained 15.9 g. of 1-(4-chlorophenylcarbamyl)-2-[2-(1-piperidyl)- ethylJpiperid-ine, M.P. 8790 C. (corn).

Analysis.Ca lcd. for C H ClN O: Cl, 10.13; N, 12.01. Found: C-1, 10.34; N, 11.96.

Example 29 completely cured the animals of the infection at a drug level of 200 mg./ kg./day.

V 7 Example 30 1 (4 nitrophenyloarbamyl)-2-[2-(4-methyl-1-piperazyl)ethyl]piperidine was prepared from 1 0.5 g. of 2-[2- .(4-methyl-1-piperazinyl)ethyl]pipe1idine and 8.2 g. of 4- nitrophenylisocyanate in 50 ml. of dry benzene using the procedure described in Example 25. Concentration of the benzene solution and tritunation of the residue with n-heyane gave a yellow solid which was collected by' filtration. There was thus obtained 14.6 g. of l-(4-nitro- 4 pheny1c-arbamyl)-2-[2-(4 methyl-l-piperazyDethyl]piperidine, M.P. 97100 C. (corn).

Analysis.Ca1cd. for C I-1 N 0 C, 60.78; H, 7.79;

. N, 18.65. Found: C, 60.70; H, 7.94; N, 18:64.

Example 31 [2-(4-methyl-1-piperazinyl)ethyl]piperidine land 7.6 g. of

4-chlorophenylisocyanate in 50 ml. of benzene using the procedure described in Example 25 There was thus obtained 16.3 g. of 1-(4-ch1orophenylcarbamyl)-2-[2-(4- methy'l-l-piperazinyDethyl]piperidine, M.P. 112-115 C. (corn).

Analysis-Calm. for C 1-I ClN O: Cl, 9.72; N, 15.35. Found: Cl, 9.60; N, 15.06.

When administered orally to hamsters with artifically induced vaginal trichomoniasis, 1-(4-ch1orophenylcarb amyl -2- [2-(4-methyll-piperazinyl) ethyl] piperidine was effective at a dose of 100 rng./kg./day.

Example 32 1 butylthiocarbamyl 2-[2-(4-methy1-l-piperazinyl) ethyl]piperidine was prepared from 10.5 g. of 2-[2-(4- methyl-l-piperazinyl)ethyl]piperidine and 5.8 g. of nbutylisothiocyanate in 50 ml. of absolute ethanol using the procedure described in Example 27. There was thus obtained 15.1 g. of l-butylthiocarbamyl-Z-[2-(4-methyll-piperazinyl)ethyllpiperidine, M.P. 677=0 C. (corn).

Analysis.--Ca1cd. for C I-1 4N 82 N, 17.16; S, 9.82. Found: N, 17.04; S, 9.60.

Example 33 1 (4 nitrophenylcarbamyl)-4-[2-(1-piperidyl-)ethyl] piperidine was prepared from 9.75 g. of 4-[2-'(1-piperidyl) ethyl]piperidine and 8.2 g. of 4-nitrophenylisocyanatein 50 m1. of dry benzene using the procedure described in Example 25 After recrystallization from benzene there was obtained 13.9 g. of 1 (4-nitropheny1carbamyl)-4-[2- (1-piperidyl)ethyl]piperidine, M.P. 176179 C. (corn).

Analysis.Calcd. for C H N O C, 63.31; H, 7.83; N, 15.54. Found: C, 63.56; H, 8.03; N, 15.80.

Example 34 1 (4 ohlorophenylthiooarbamyl)-2-[2-( l-hexamethyleniminyl)ethyl]piperidine was prepared from 10.5 g. of 2-[2-(l-hexamethyleniminyl)ethyl1piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 50 n11. of absolute ethanol using the procedure described in Example 27. There was thus obtained 10.6 g. of 1-(4-ch1orop'henylthiocarbamyl) 2-[2-(1-hexamethylenirninyl)ethyl]piperidine, M.P 159162 C. (corn).

Analysis.Calcd. for C H ClN S: N, 11.06; S, 8.44. Found: N, 11.05; S, 8.71.

Example 35 Example 36 v v 1 (4 nitrophenylcarbamyl) -2-[2-('1,2,3,4-tetrahydroisoquinolyl-Z)ethyHpiperidine was prepared from 12.2 g.

of 2 [2-(1,2,3,44tetrahydroisoquinolyl-2)ethyl]piperidine and 8.2 g. of 4-nitrophenylisocyanate in ml. of dry benzene using the procedure described in Example 25. There was thus obtained 15.1 g. of 1-(4-nitropheny1carlbamyl) 2 -[2-(1,2,3,4-tetrahydroisoquinolyl- 2)ethyl]piperidine, M.P. ISO-154 C. (corn).

5.3 Analysis.-Calcd. for C H N O C, 67.72; H, 6.91; N, 13.72. Found: C, 67.51; H, 6.87;. N, 13.89.

Example 3 7 1 (4 nitrophenylcarbamyl)-2-[2-(l-piperidyDethyl] piperidine was prepared from 9.75 g. of 2-[2-( l-piperidyl) ethylJpiperidine and 8.2 g. of 4-nitrophenylisocyanate in 50 ml. of dry benzene using the procedure described in Example 25. There was thus obtained 16 g. of 1-(4-nitrophenyloarbamyl) -2-[2-( l-piperidyl)ethyllpiperidine, M.P.

139141 C. (corn).

Analysis.-Calcd. for O l-1 N C, 63.31; H, 7.83;

N 3.88. Found: C, 63.32; H, 7.61; N 3.79.

Example 38 1 (4 nitrophenylcarbamyD-Z-[Z-(4-phenyl-1-piperazinyl)ethyl]piperidine was prepared from 13.7 g. of 2-[2- (4-phenyl-1-piperazinyl)ethylJpiperidine and 8.2 g. of 4- nitro phenylisocyanate in 30 ml. of dry benzene using the procedure described in Example 25. There was thus obtained 18 g. of 1( 4-nitrophenylearbamyD-2-[2-(4- phenyl-l-piperazinyDethyl]piperidine, M.P. 148-150 C. (corn).

Analysis.-Calcd. for C H N O C, 65.88; H, 7.14; N, 16.01. Found: C, 65.63; H, 6.89; N, 16.20.

Example 39 1 (4 ehlorophenylthiocarbarnyl)-2-[2-(4-phenyl-1- piperazinyl)ethyl]piperidine was prepared from 13.7 g. of 2 [2 (4-phenyl-l-piperazinyl)ethyl]piperidine and 8.5. g. of 4-ch1orophenylisothiocyauate in 50 ml. of absolute ethanol using the procedure described above in Example 27. There was thus obtained 21.2 g. of 1-(4-chloropheny1- thiocarbamyl) 2 [2 (4-phenyl-1-piperazinyl)ethyl] piperidine, M.P. 182184 C. (corn).

Analysis.-Calcd. for C H C1N S: Cl, 8.00; S, 7.24. Found: Cl, 7.94; S, 7.05.

Example 40 1 (4 chlorophenylthiocarbamyl) 2 [2 (1,2,3,4- tetrahydroisoquinolyl-Z)ethyl]piperidine was prepared from 12.2 g. of 2-[2(1,2,3,4-tetrahydro-2-isquino1yl) ethyl1piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 80 ml. of absolute ethanol using the procedure described in Example 27. There was thus obtained 16.7 g. of 1-(4-chlorophenylthiocarbamyl) -2-[2-(1,2,3,4-tetrahydroisoquinolyl-Z)ethylJpiperidine, M.P. 187493 C. (corn).

Analysis.-Calcd. for C H C1N S: Cl, 8.57; N, 10.15; S, 7.74. Found: Cl, 8.40; N, 10.23; S, 7.73.

Example 41 1 (4 chlorophenylthiocarbamyl) 2 [2 (4 morpholinyl)ethyl]piperidine was prepared from 12.2 g. of 2-[2-(4-morpholinyl)ethyl]piperidine and 8.5 g. of 4- chlorophenylisothiocyanate in 80 ml. of absolute ethanol using the procedure described in Example 27. The 15.5

g. of l-(4-chlorophenylthiocarbamyl)'-2-[2-(4-morpholinyl)ethy1]piperidine thus obtained had the M.P. 158- 1 61" C. (corn).

Analysis.Calcd. for c n ciruos; Cl, 9.64; S, 8.71. Found: Cl, 9.73; S, 8.50.

When administered orally to rats infected with the roundworm Strongyloides rattz', l-(4-chlorophenylthiocarbamyl) -2 [2- (4-morpholinyl) ethyl] piperidine complete- 1y cured the animals of the infection at a drug level of 200 mg./kg./day. The oral toxicity was found to be 7400:1950 rug/kg. in twenty-four hours and 2300:643 nag/kg. in seven days.

Example .42

1 (N,N diethylcarbamyl) 2 [2 (l pyrrolidyl) ethylJpiperidine: To a solution of 27.3 g. of 2-[2-(1- pyrrolidyl)ethyl]piperidine in 100 m1. of dry benzene in a three-necked round bottom flask was added 12.6 g. of sodium bicarbonate. The resultant suspension was 16 rapidly stirred while 20.4 g. of diethylcarbamoyl chloride in 50 ml. of dry benzene was added. After the addition was complete the mixture was stirred for one hour. The

solid which separated was removed by filtration and the Example 43 1 (4 ethoxyphenylthiocarbamyl) 2 [2 (4- methyl-l-piperazinyl)ethyllpiperidine was prepared from 10.6 g. of 2-[2-(4-methyl-l-piperazinyl)ethyl]piperidine and 8.97 g. of 4-ethoxyphenylisothiocyanate in ml.

of absolute ethanol using the procedure described in Example 25. The l-(4-ethoxyphenylthiocarbamyl)-2-[2- (4-methyl-1-piperazinyl)ethyl]piperidine thus obtained weighed 17.3 g. and had the M.P. 147-148" C. (corn).

Analysis.-Calcd. for C H N,,OS: N, 14.35; S, 8.21. Found: N, 14.29; S, 8.18.

Example 44' 1 phenylthiocarbamyl 2 a [2 (4 methyl 1 piperazinyDethylJpiperidine was prepared from 10.5 g. of 2- [2-(4-methyl-1-piperazinyl)ethyljpiperidine and 6.7 g. of phenylisothiocyanate in 60 ml. of absolute ethanol using the procedure described in Example 27. There was thus obtained 11 g. of l-phenylthiocarbamyl-Z-[2-(4-methyll-piperazinyl)ethy11piperidine, M.P. ill-119 C. (corn).

A nalysis.Calcd. for CmHoNgSZ Nt t 16.17; N 8.08. Found: Nt g Naming, 8.09.

Example 45 1 (4 chlorophenylthiocarbamyl) 2 -[2 (1 pyrrol idyl)ethyl]piperidine was prepared from 9.1 g. of 2-[2- (l-pyrrolidy1)ethyl] piperidine and 8.5 g. of 4-chlorophenylisothiocyanate is ml. of absolute alcohol using the procedure described in Example 27 There was thus obtained 15.8 g. of 1-(4-chlorophenylthiocarbamyl)-2- [2-(l-pyrrolidyl)ethyllpiperidine, M.P. 148-150 C. (corn).

Analysis.-Calcd. for C H ClN S: Cl, 10.08; S, 9.11. Found: Cl, 10.25; S, 9.03.

Example 46 1 (4 chlorophenylthiocarbamyl) 2 [2 (1 piper.- idyl)ethyl]piperidine was prepared from 9.75 g. of 4-[2- (1-piperidyl)ethyl] piperidine and 8.5 g. of 4-chlorophenyl isothiocyanate in 80 ml. of absolute alcohol using the procedure described in Example 27. The 1-(4-chlorophenylthiocarbamyl) 4 [2 (1 piperidyDethyl] piperidine thus obtained weighed 11 g. and had the M.P. 136-148 C. (corn).

Analysis.-Calcd. for C H ClN S: Cl, 9.69; S,- 8.76. Found: Cl, 9.87; S, 8.75.

Example 47 1 (4 chlorophenylthiocarbamyl) 5 ethyl 2 [2- (1-piperidyl)ethyl]piperidine was prepared from 11.1 g. of 2-[2-(1-piperidyl)ethyl] -5-ethylpiperidiue and 8.5 g. of 4-chlorophenylisothiocyanate in 80 ml. of absolute ethanol using the procedure described in Example27. There was thus obtained 13.5 g. of '1-(4-chlorophenylisocarbamyl)-5-ethyl- 2-[2-(1-piperidyl)ethyl] piperidine,

178-185 C. (corn). 7

Analysis.-Calcd. for C I-I ClN S: N, 10.66; S, 8.14. Found: N, 10.72; S, 8.17.

When administered orally to rats infected with the 17 round worm Strongyloides ratti, =1 (4-chlorophenylthiocarbamyl) -5-ethy1-2 [2- l-piperidyl) ethyl] piperidine completely cured the animals of the infection at a drug level of 100 mg./kg./day. The oral toxicity was found to .be 8000 mg./kg. in twenty-four hours and 2000x324 mg./kg. in seven days.

Example 48 1 (4 chlorophenylthiocarbamyl) 4 [2 4 (l hexamethyleniminyl)ethyl]piperidine was prepared from 10.5 g. of 4- [2-(l-hexamethyleniminyl)ethyl]piperidine and 8.5 g. of 4-chlorophenylisocyanate in 70 ml. of absolute ethanol using the procedure described in Example 27. There was thus obtained 8 g. of 1- (4-chlorophenylthiocarbamyl) 4 [2 (1 hexamethyleniminyl)ethyl]piperidine, M.P. 120-122 C. (corn).

.Analysis.Calcdl for C H dclN Sz Cl, 9.33; S, 8.44. Found: Cl, 9.54; S, 8.56.

Example 49 l (4 chlorophenylthiocarbamyl) 2 [2 (4- methyl-l-piperidyl)ethyl]piperidine .was prepared from 10.5 g. of 2-[2-(4-methyl-l-piperidyl)ethyl]piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 80 m1. of absolute ethanol using the procedure described in Example 27. The 1-(4-chlorophenylthiocarbamyl)-2-[2-(4- methyl-l-piperidyl)ethyl]piperidine thus obtained weighed 15.1 g. and had the M.P. 159-161 C. (corn).

Analysis.'-Ca1cd. for C H ClN S: Cl, 9.33; S, 8.44. Found: Cl, 9.67; S, 8.27.

Example 50 1-(4 chlorophenylthiocarbamyl) 2-[2-(2-methoxyanilino)-ethyl]piperidine was prepared from 11.7 g. of 2-[2-(2-mthoxyanilino)ethyl]piperidine and 8.5 g. of 4- chlorophenylisothiocyanate in 80 m1. of absolute ethanol using the procedure described in Example 27. There was thus obtained 14.4 g. of 1-(4-chlorophenylthiocarbamyl)- 2-[2( methoxyani1ino)ethyl]piperidine, M.P. 152l54 C. (corn).

Analysis.-Calcd. for C H ClN OS: Cl, 8.78; S, 7.94. Found: Cl, 8.65; S, 7.78.

Example 51 1-(4 chlorophenylthiocarbamyl) 2 (diethylaminoethyl) piperidine was prepared from 9.2 g. of 2-(2-diethylaminoethyDpiperidine and 8 .5 g. of 4-chlor'ophenylisothiocyanate in 60 ml. of absolute ethanol using the procedure described in Example 27. There was thus obtained 12 g. of 1-(4-chlorophenylthiocarbamyl)-2-(diethylaminoethyl)piperidine, M.P. l30132 C. (corr.

Analysis.Calcd. for C H ClN S: 01, 10.02; s, 9.06. Found: Cl, 10.33; S, 8.97. l l 7 Exampl 52 1 allylthiocarbambyl 2-{2-(4-methyH-pip razinyl) et hyl]piperidine was prepar'edfrom 10.6 g. of 2-[2-(4- methyl-l-piperazinyl)ethylJpiperidihe and g. of allylisothiocyanate in 60 ml. of absolute ethanol using the procedure described above in Example 27. There was thus obtained 9.7 g. of1-allylthiocarbamyl 2-[2-(4-methyl-lpiperazinyDethyl]piperidine, M.P. 9091. C. (corr.).

Analysis.Calcd. for C16H30N4SI N, S, Found: N, 18.13; S, 10.24.

Example 5 3 1 (4 chlorophenylthiocarbamyl)-2-[2-(2,6'-dimeth- 'yl-4-morpholinyl)ethylJpiperidine was prepared from 11.3 g. of 2-[2(2,6-dimethyl-4-morpholinyl)ethyl]piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 80 ml. of

absolute. ethanol usingthe procedure described in Example 27. The 13.3 g. of 1-(4-chlorophenylthiocarbamyl)- 2- 2- 2,6-dimethyl-4-morpholinyl -ethyl] piperidine thus obtained had the M.P. 174-176 C. (corn).

Analysis.-Calcd. for C H ClN OS: Cl, 8.95; N,

10.61 S, 8.10. Found Cl, 9.41; N, 10.30; S, 8.24.

.Found: Cl, 9.05;;S, 8.03.

When administered orally to rats infected with the roundworm Strongyloides ratti, 1-(4-chlorophenylthiocarbamyl)-2[2-(2,6 dimethyl 4-morpholinyl) ethyl] piperidine completely cured the animals of the infection at a drug level of 100 mg./kg./day. The oral toxicitywas found to be 8000 in twenty-four hours and 6000 mg./ kg. in seven days.

Y Example 54 Found: Cl, 8.90; N, 13.74.

Example 55 1 (4 chlorophenylthiocarbamyl)2-(2-anilinoethyl) piperidine was prepared from 10.2 g. of 2-(2-anilinoethyl) piperidine and 8.5 of 4-chlorophenylisothiocyanate in ml. of absolute ethanol using the procedure described in Example 27. There was thus obtained 10 g. of 1-(4-chlorophenylthiocarbamyl) 2 (2-anilinoethyl)piperidine, M.P. 174-175 C. (corn).

Analysis.--Calcd. for C H ClN S: Cl, 9.48; S, 8.57. Found: Cl, 9.45; S, 8.54.

Example 56 1 (4 chlorophenylthiocarbamyl)2-[2-(l-hexamethyleniminyl)ethyl]-5-ethylpiperidine was prepared from 11.9

g. of 2-[2-( l-hexamethyleniminyl)ethyl] -5-ethylpiperidine and 8.5 g. of 4-chlorophenylisothiocyanate in ml. of absolute ethanol using the procedure described in Example 27. There was thus obtained 15.3 g. of 1-, (4-chlorophenylthiocarbamyl) 2 [2 (l-hexamethyleniminyl) ethyHS-ethylpiperidine, M.P. 168-170 C. (corn).

Analysia-C alcd. for C H ClN S: Cl, 8.69; S, 7.86.

Found: Cl, 8.50; s, 7.98.

When administered orally to rats infected with the roundworm Strongyloides ratti, 1-(4-chlorophenylthiocarbamyl')-2-[2-(l-hexamethylenirninyl)ethyl] --5 ethylpiperidine completely cured the animals of the infection at a drug level of mg./kg./day. The oral toxicity was found to be 4000 mg. /kg. in twenty-four hours and'2280:490mg./kg..in seven days'.

Example 57 1 (4 chlorophenylthiocarbamyl) -2-[2-'(4-ethyl-1- piperazinyl)ethyl]piperidine was prepared from 11.25 g. of 2-[2-.(4-ethyl-1-piperazinyl)ethyl]piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 70 ml. of absolute .ethanol using the procedure described in Example27. There was thus obtained 9.8g. of 1a(4-chlorophenylthiocarbamyl) 2 [2 (4-ethyl-1rpiperazinyl)ethyl]piperidine, M.P. 153154 C. (corn): .Analysis.+Calcd. for C H Cl'N S: Cl, 8.98; S,-8..12.

'Example 58 1 '4 chlorophenylthiocarbamyl) 4 2 1',2, 3,4- .tetrahydroisoquinolyl-2)ethyl]piperidine was prepared from 12.2 g. of .4-[2-(1,2,3,4-tetrahydro-2-isoquinolyl)- ethyl]piperidine and 8.5 g. of -4-chlorophenylisothiocyanate in 80 ml. of absolute ethanol using the procedure described in Example 27. There, was thus obtained 16.2 g. of 1 (4 chlorophenylthiocarbamyl)-4 [2-(1,2,3,4-

.tetrahydroisquinolyl-2)ethyl]piperidine, M.P. '157 .C. (corn).

Analysis.--Calcd. for C H ClN S: (:1, 3.57; s,.7.74.

Found: 01, 8.63; s, 1.98..

19 Example 59 1 l (3,4 dichlorophenylthiocarbamyl) 2 [2 (1- hexamethyleniminyl) ethyl] piperidine was prepared from 10.5 g. of 2-[2-(l-hexamethylenirninyl)ethyl1piperidine and 10.2 g. of 3,4-dichlorophenylisothiocyanate using the procedure described in Example 27. The 13.6 g. of 1 (3,4 dichlorophenylthiocarbamyl) 2 [2 (1- hexamethyleniminyl)ethyl]piperidine thus obtained had the M.P. 156-158 (corn).

Analysis.-Calcd. for C H Cl N S: Cl, 17.11; S, 7.74. Found: Cl, 17.40; S, 7.80.

Example 60 1-(4-chlorophenylthiocarbamyl)-5-ethyl-2- [2-(4 morpholinyDethyHpiperidine was prepared from 11.3 g. of 2-[2-(4-morpholinyl)ethyl]-5-ethylpiperidine and 8.5 g.

of 4-chlorophenylisothiocyanate in 80 m1. of absolute ethanol using the procedure described above in Example 27. There was thus obtained 14.5 g. of 1-(4-chlorophenyl thiocarbamyl) --ethyl-2- [2- (4 morpholinyl) ethyl] piperidine, M.P. 171-17680. (corn).

Analysis. Calcd. for C H CIN OS: Cl, 8.95; S, 8.10. Found: Cl, 8.82; S, 8.17.

Example 61 l 1- (4-chlorophenylthiocarbamy1)-2- [2-(5 ethyl-Z-methyl-l-piperidyl)ethyljpiperidine was prepared from 11.9 g. of 2-'[2-(2-methyl-5-ethyl-1-piperidyl)ethyl]piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 80 ml. of absolute ethanol using the procedure described in Example 27.

There was thus obtained 3.7 g. of l-(4-chlorophenylthiocarbamyl)-2-[2-(5-ethyl-2-methyl 1 piperidyl)ethyl]piperidine, M.P. 160-162 C. (corn).

Analysis-Called. for C22H34C1N3S: Cl, 8.69; S, 7.86. Found: Cl, 8.95; S, 7.93.

Example 62 1-(4-ch1orophenylthiocarbarnyl)-4-[2- (4-methyl 1 piperazinyDethyl}piperidine Was prepared from 10.6 g. of 4-[2-(4-methyl-1-piperazinyl)ethylJpiperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 65 ml. of absolute ethanol using the procedure described in Example 27. The 139g. of 1-(4-chlorophenylthiocarbamyl)-4-[2-(4- 'methyl-1-piperazinyl)ethylJpiperidine thus obtained had the M.P. 134l37 C. (corn).

Analysis.-Calcd. for C H ClN S: Cl, 9.31; S, 8.41. Found: C], 9.45; S, 8.53.

Example 63 1-(2-chlorophenylcarbamyl) 2 [2 (4- morpholinyl) ethyl1piperidine was prepared from 9.85 g. of 2- [2-(4-morpholinyl) ethyljpiperidine and 7.6 g. of 2-chlor0phenylisocyanate in 50 ml. 'of'dry be'nzeneusingthe procedure described in Example 25. There was thus obtained 12.9

g. of 1-(2-[2-(4-morpholinyl)ethyl]piperidine, M.P. 119- 120 C. (corn).

11.94., Found: Cl, 9.88; N, 11.92.

Example 64 i .l-(4-ch1orophenylthiocarbamyl) 2-(2-anilinoethyl)-5- ethylpiperidine was prepared from 11.6 g.-of 2-(2-anilinoethyl)-5-ethylpiperidine.and 8.5 g. of 4-chlorophenylisothiocyanate in 80 ml. of absolute ethanol using the procedure described in Exarnple 27. There was thus obtained 3.1 g. of l-(4-chlorophenylthiocarbamyl)-2 (2-anilin0- 'Analysisr-Calcd. for C H C1N O 10.08; N,

ethyl)-5-ethyl-piperidine, M.P. 215-224 C. (corn).

Analysis.Calcd. for (2 11 01151 8: 01, 8.82; s, 7.98.

Found: Cl, 9.15; s, 7.88.

Example 65 l-(4-chlorophenylthiocarbamyl) 2 [2 (Z-methylanilino)ethyl]piperidine was prepared from 10.8 g. of 2-[2- (2-methylanilino)ethyl]piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 80 m1.-of-absoluteethanol-using the procedure described in Example 27. 'The 11.7 'g.'of

1-(4-chlorophenylthiocarbamyl) 2-'[2-(2-methylanilino) ethyl] piperidine thus obtained had the M.P. 171-174" C. (corn).

Analysis.Calcd. for c u clmsz Cl, 9.14; S, 8.26. Found: Cl, 8.90; S, 8.23.

Example 66 Example 67 1-(4-chlorophenylthiocarbamyl) 5 ethyl-2-I2-(l-pyrrolidyl)ethyl]piperidine was prepared from 10.5 g. of 2- [2-(l-pyrrolidyl)ethyl]piperidine and 8.5 g. of 4chlorophenylisothiocyanate in 80 m1. of absolute ethanol using the procedure describedin Example 27. There was thus obtained 12.7 'g. of 1-(4-chlorophenylthiocarbamyl)-5- ethyl-2-[2-(1-pyrr0lidyl)ethyl]piperidine, M.P. 183-184 C. (corn).

Analysis.Calcd. for C H ClN S: Cl, 9.33; S, 8.44. Found: Cl, 9.24; S, 8.58.

When administered orally to rats infected with the roundworm Szrqngyloz'des ram, l-(4-chlorophenylthiocarbamyl) -5-ethyl-2- [2-( I pyrrolidyl) ethyl] piperidine completely cured the animals of the infection at a drug level of mg./kg./day. The oral toxicity was found to be 4000 mg./kg. in twenty-four hours and 2280:490 mg./ kg. in seven days.

Example 68 1-(4-chlorophenylthiocarbarriyl) 2- [2-(1-decahydroquinolyl)ethyl]piperidine was prepared from 12.5 g. of

2-[2-(l-decahydroquinolyl)ethyHpiperidine and 8.5 g. of 4-chlorophenylisothiocyanate in ml. of absolute ethanol using the procedure described in Example 27. There was thus obtained 4.2 g. of 1-(4-chlorophenylthiocarbamyl)- 2-[2-( 1-decahydroquino1yl)ethy1]piperidine, M.P. 171- 174 C. (corn).

A-nalysis.Calcd. for C H ClN- S: Cl, 8.44; S, 7.63.

Found: Cl, 8.20; S, 7.77.

I Example 69 1-(4-chlorophenylthiocarbamyl) 2-[2-(2,6 dimethyllmorpholinyl)ethyl]-5-ethylpiperidine was prepared from 12.7 g. of 2-[2-(2,6-dimethyl-4-morpholinyl)ethyl]-5-ethylpiperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 80 ml. of'ab'solute ethanol using the procedure described in Example 27. There was thus obtained 10.9 g. of 1-(4- chloropheuylthiocarbamyl)-2-i[2-(2,6-dimethyl '4 1 morpholinyl) ethy1]-S-ethylpiperidine, M.P. 19 8-199 C. (corn).

Analysz's.--Calcd. for C H C1N OS: Cl, 8.36; N, 9.91. Found: Cl, 8.35; N, 10.22.

Example 70 1-( 4-chlorophenylthiocarbamyl) -4- [2-( 4 morpholinyl) V ethyl] piperidine was prepared from 9.9 g. of 4-[2-(4-morpholinyl)ethyl]p iperidine and 8.5 g..of 4-chlorophenylisothiocyanate in 80ml. of absolute ethanol using the pro-- cedure described in Example 27. I There was this 012- tained 14.4 g. of 1(4-chlorophenylthiocarbamyl)-4-[2-(4- morpholinyl)ethyljpiperidine, M.P. 134-136 C. (corn). AnalysislCalcd. for C l-l gClN Osz Cl, 9.64; S, 8.71. .Found C1',9.' 70; S, 8.83.

Example 71 1 (4 chlorophenylcarbamyl) 2-{2-(4-phenyl-1-piperazinyl)ethyl]piperidine was prepared from 13.7 got 2-[2- 5 (4-phenyl 1 piperazinyl)ethyl]piperidine and 7.7 g. of 4-chlorophenylisocyanate in 50 ml. of dry benzene using the procedure described in Example 25. There was thus obtained 11.7 g. of 1-(4-chlorophenylcarbamyl)-2-[2-(4- phenyl-l-piperazinyl)ethyl]piperidine, M.P. 144-145 C. (corn).

Analysis.-Calcd. for C H 'C1N O: C, 67.51; H, 7.13; Cl, 8.54. Found: C, 67.46; H, 7.13; Cl, 8.54.

Example 72 1 (2 chlorophenylthiocarbamyl) 2 [2-(1 hexa' methyleniminyl)ethyl]piperidine was prepared from 10.5 g. of 2-[2(1 hexamethyleniminyl)ethyl]piperidine and 8.5 g. of 2-chlorophenylisothiocyanate in 60 m1. of absolute ethanol using the procedure described in Example 27. There was thus obtained 16.3 g. of 1-(2-chlorophenylthiocarbamyl)-2-[2 (1 hexamethyleniminyl): ethy1]piperidine, M.P. 115118 C. (corn).

Analysis.Calcd. for C H CIN S: Cl, 9.33; N, 11.06. Found: Cl, 9.35; N, 11.21.

Example 73 1 (2 ethoxyphenylcarbamyl) 2 [2-(1-piperidy1) ethyl]piperidine was prepared from 9.8 g. of 2-[2-(1- piperidyl)ethyl]piperidine and 8.2 g. of Z-ethoxyphenylisocyanate in 50 ml. of dry benzene using the procedure described in Example 25. The mixture was cencentrated at reduced pressure and the residue distilled to give 12.7 of 1- (2-ethoxyphenylcarbamyl) -2- [2- (2-piperidy1) ethyl] piperidine, B.P. 130.2/0.21 mm.

Analysis.-Calcd. for C H N 02l Nt t N 3.89. Found: N 11.77; N 4.18.

Example 74 1 (N,N-dimethylcarbamyl)-2-[2-(1-pyrrolidyl)ethyl]- piperidine was prepared from 27.3 g. of 2-[2-(1 pyrrolidyl)ethyl]piperidine, 12.6 g. of sodium bicarbonate and 16.1 g. of dimethylcarbamoyl chloride in 150 ml. of dry benzene using the procedure described in Example 42. There was thus obtained 8.8 g. of l-(N,N-dimethylcarbamyl)-2-[2 (1 pyrrolidyl)ethyl]piperidine, B.P. 118- 119 C./0.15 mm. 5 I Analysis.Calcd. for C H N O: Nm 16.58; N 5.53. Found: N 16.49; N 5.37.

Example 75 1 (2 methoxyphenylcarbamyl)-2-[2-(4-niethy1-1- piperazinyl)ethyl]-5-ethylpiperidine was prepared from 12 g. of 2-[2-(4-methyl-l-piperazinyl)ethyl] -5-ethylpiperidine and 7.5 g. of 2-rnethoxyphenylisocyanate in 50 m1. of dry benzene 'usingthe procedure described in Example 73; There was thus obtained, 7.2 g. of 1-(2-methoxyphenylcarbamyl) -2 [2(4-methyl-l-piperazinyl)ethyl1-5- ethylpiperidine, B.P. 129133 C./0.23 mm.- Ar zalysis. Calcd. for C22H N Og: N t N 7.27. Found: N 14.35; N 7.43.

Example 76 1 (2 --chlorophenylcarbamyl)-2 [2 (2,6 dimethyl-4- morpholinyl)ethyl]piperidine was preparedfrom 11.3 g. of 2 [2 (2,6-dimethyl-4 morpholinyl)ethylJpiperidine .and 7.7 g. of 2-chlorophenylisocyanate in 50 ml. of, dry

benzene using the 'procedure described in Example 73. There -was t hus obtained 12.5 g. of 1- '(2 chlorophenylcarb amyl 2% [2- 2,6-dimethyl-4-morpholinyl) ethyl jpi per idine, lV.LPl1O8"109 C. (60113). i l I "11.06. Found: 01, 9.27;'N,1 1 .01'. p Example. 77 Q 1 (4' chlorophenylthiocarbamyl)-2 [2 (4 hydroxy'- 'ethyl l -piperazinyl)ethyIJpiperidinev was prepared from 112.05 g. of 2-[2-(4-hydroxyethyl-l-piperazinyl)ethyl]piperidine and 8.5 g. of.4-chlorophenylisothiocyanate in ml. of absolute ethanol using the procedure described 22 above in Example 27. There was thus obtained 10 g. of 1-(4-chlorophenylthiocarbarnyl)-2 [2-(4-hydroxyethy1 l-piperazinyl)ethyl]piperidine, M.P. 154-155 C. (corn).

Analysis.Calcd. C2oH31C1N4OS: C1, S,7.80- Found: Cl, 8.40; S, 8.05.

Example 78 I 1 (4 chlo'robenzylthiocarbamyl)-2-[2- (1 hexamethyleniminyl)ethy1]piperidine was prepared from 10.5 g. of 2- [2-(1-hexamethylenimnyl)ethyl]piperidine and 9,2 g. of 4-chlorobenzy1isothiocyanate in-50 ml. of abso lute ethanol using the procedure described in Example 27. There was thus obtained 14.4. g. of 1-(4-chlorm benzylthiocarbamyl) 2 [2 1 hexamethyleniminyD- ethyl]piperidine, M.P. 107-108 C. (corn).

Analysis.Calcd. for C H ClN S: N, 10.66; S, 8.14. Found: N, 10.80; S, 8.35.

Example 79 1 diethylcarbamyl 2 2 (4-methyl-1-piperazinyl) ethyl]piperidine was prepared from 21.1 g. of 2-[2(4- methyl-l-piperazinyl)ethyl]piperidine, 8.4 g. of sodium bicarbonate and 13.6 g. of diethylcarbamoyl chloride in 110 m1. of dry benzene ,using the procedure described in Example 42. There was thus obtained 9.8 g. of l-diethylcarbamyl 2 [2 (4-methyl-1-pipera'zinyl)ethyl]piperidine, B.P. C./0.03 mm.

Analysis.--Calcd. for C H N O: C, 65.76; H, 11.04;

N, 18.05. Found: @6563; H, 11.29;,N, 17.92. I

1 7 Example 80 v I I p 1 (4 chlorophenylthiocarbamyl)-2-[2-(3-methy1-lpiperidyl)ethyl]piperidine was prepared from 10.5 g. of 1-[2-(3-methy1-l-piperidyl)ethyl]piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 75 ml. of absolute ethanol using the procedure describedabovein Example 27.'

There was thusobtained 14 g. of 1-(4-chlorophenylthiocarbarny) -2-[2 -,(3. methyl-l-piperidyl)ethyl]piperidin M.P. 148-149 C. (corn). Analysis.Calcd. for C H ClN S: Cl, 9.33; N, 11.06.

Found: Cl, 9.50; N, 11.06.

Y Example 81 1 (4 bromophenylthiocarbamyl)#2-[2 (1 hexamethyleniminyl)ethyl]piperidine was prepared from-10.5 g. of. 2- [2-(1-hexamethyleniminyl)ethyl]piperidine and 10.7 g. of 4-bromophenylisothiocyanate in 75ml. of absolute alcohol using the procedure described above in Example 27. There was thus obtained16 g. .of 1-(4; bromophenylthiocarbamyl) 2 [2- (1 -hexame thyleniminyl(ethyl]piperidine, M.P. 167-168 C." (corn).

Analysis.-Calcd. for C H BrN S: Br, 18.83; N, 9.90. Found: Br, 18.50; N,11 0.1 0.

.. Example 82 n i 1 (4 chloroph'enylthiocarbamyl)-5-ethyl=2-[2-(4- methyll-piperidyl(ethylJpiperidine was prepared from 2[2'-(4 7 methyl- Lpiptidyl)ethyl1-5-ethylpiperidine and 8.5g. of 4-chlorophenylisothiocyanate in 75,1111. of abso; lute ethanol using the procedure described in Example 27. There wasthus obtained 6 g2 offl-(4-chlor'ophenylthiocarbamyl') 4 ethyl '2"- [2 (4-'methy 1-piperidyl) ethyHpiperidine, M.P. 173175 C; '(corr.

Analysis.Calcd. f0r"C H .,ClN S: 01, 8.69; N, 10.30.

23 A naZys.Ca1cd. for c22H N O Nt N 3.76. Found: N 15.06; N 3.88.

' Example 84' 1-(4-chlorophenylthiocarbamyl) 2 a [2 (4 -ethyl-1- piperazinyl)ethyl]piperidine was reported from 12.6 g. of 2-[2-(4-ethyl-1-piperazinyl)ethyl]piperidine and 8.5 g. of 4-chlorophenylisothiocyanate in 75 ml. of absolute an anol using the procedure described in Example 27. There Was thus obtained 3.3 g. of 1-(4-chlorophenylthiocarbamyl) 2 [2 (4 ethyl-l-piperazinyl) ethylJpiperidine, M.P.'104105 C. (corn).

Analysis.Calcd. for C H ClN S: Cl, 8.38; N 6.62. Found: Cl, 8.23; N 6.66 Y

Example 85 1-(4-nitrophenylcarbarnyl) 2 [2 (4 morpholinyD- ethyl1piperidine was prepared from 9.9 g. of 2-[2-(4- morpholinyl)ethy1]piperidine and 8.2 g. of 4-nitrophen ylisocyana'te in 130 ml. of dry benzene using the procedure described above in Example25. Recrystallization from adioxane-pentane mixture gave 14.7 g. of 1-(4- nitrophenylcjarbarnyl)-2-[2-(4 morpholinyDethylJpiperidine, M.P. 138-139 C; (corn).

Analysis.Calcd. for C H N O C, 59.65; H, 7.23; N 3.87. Found: C,.59.18; H, 6.92;'N 3.86.

Example 86 1-(3-chlorophenylthiocarbamy1)-2-[2 (1 -hexan1ethylenirninyl)ethyllpiperidine was prepared from 10.5 g. of 2-[2-(l-hexarnethyleniminyl)ethyllpiperidine and 8.5 g. of 3-chloropheny1isothiocyanate in ,75 ml. of absolute ethanol using the procedure described in Example 27. After recrystallization from absolute ethanol there was obtained 17 g. of- 1-(3-chlorophenylfniocarbamyl)-2-[2- (l-hexamethylenirninyl) ethy1]piperidine, M.P. 104105 C. (com).

Analysis..-Calcd. for C H CIN S: Cl, 9.33; S, 8.44. Found: Cl, 9.37; S, 8.58.

r Example 87 v 1-(2-chlorophenylthiocarbamyl) -2-[2 (1 piperidy1)- ethyl]-5-ethylpiperidine was prepared from 11.1 g. of

2-[2'-.(1-piperidy1)ethyl]-5-ethylpiperidine and 8.5 g of 2-chlorophenylisothiocyanate in ml. of absolute ethanol using. the procedure described in Example 27. Recrystallization from ethanol gave 11.7 g. of 1-(2-chlorophenylthiocarbamyl)-2-[2-(l-piperidyljethyl] 5 ethylpiperidine, M.P. 101102 C. (corn).

I Analysia-Calcd. for C H ClN S: Cl, 9.00; S, 8.14. Foundz'Cl, 9.09; S, 8:13..

' 'Example88 1-(2-chlorophenylthiocarbamyl) 2 1-pyrrolidyl)- ethyH-S-ethylpiperidine was prepared from 10.5 g. of

2-[2-(1-pyrrolidyl)ethyl]-5-ethylpiperidine and 2-c hlorophenylisothiocyanate in 55 m1. of absolute ethanol using the procedure described in Example 27. 'After recrystallization from absolute ethanol there was obtained 14 g.

of 1- 2 chlorophenylthiocarbamyl)-2-[2-( l pyrr'olidyl} I ethyll-S-ethylpiperidine, M.P. 115-116 C. (corn).

AnalySis.Calcd. for C TI ClN SL 9.33; S. 8.44. Found: Cl,9.41;S, 8 .43.-. 1

' Example 89 1-(2-chlorophenylthiocarbamyl) 2 [2'- (4-rnethy1-1- piperazinyl)ethylJpiperidine was-prepared from 10.25 g. of 2-[2-(4-rnethyl-1-piperazinyl)ethyIJpi eridine and 8.5 g. of; 2-chloropheny-lis'othiocyanatein 50 rnhof absolute ethanol using the procedure described above in Example Q -27." Recrystallization froma pentane-benzene mixture gave 8.6g. of 1-(2-chlorophenylthiocarbarnyl)-2 [2-(4 methyl-1-piperazinyl)ethyHpiperidine, M.P. 1286-1292? C. (corn). p v

.AnaIysis.-Calcd. tor C H ClN S: Cl, 9.31; 8,841. Found: Cl, 9.41;S, 8.62.

Example 90 1-(N,N-diethylcarbamyl) 2 [2-(4-morpholinyl)ethylJpiperidine was prepared from 8.4 g. of sodium bicarbonate, 19.7 g. of 2-[2-(4-rnorpholinyl)ethylJpiperidine and "13.6 g. of diethylcarbamoyl chloride in ml. of dry benzene using the procedure described in Example 42. There was thus obtained 8.3 g. of 1-(N,N-diethylcarbarnyl) -2 [2 --'(4-rnorp'holinyl)ethyl]piperidine, B.P. 126 C./0.08 mm.

Analysis-Calm. for C I-1 N 0 C, 64.61;H, 10.51;

N, 14.13. Found: C, 64.70; H, 10.58; N, 14.05.

' Example 91 1-(N,N diethylcarbarnyl) 2 [Z-(I-heXa nethyIeniminyl)ethyl]piperidine was prepared from 8.4 g. of sodium bicarbonate, 21 g. of 2-[2-(1-hexamethyleniminyl)ethyl] piperidine and 13.6 gfof diethylcarbamoyl chloride in 110 ml. of dry benzene using the procedure described in Example 42. There was thus obtained 5.5 g. of l-(N, N-diethylcarbamyl -2- [2- 1 hexarnethyleniminyl) ethyl] piperidine, 13.1. 152 C./0.5 mm.

Analysis.-Calcd. for C H N O: C, 69.85; H, 11.40;

N, 13.58. Found: C, 70.14; H, 11.13; N, 13.58.

Example 92 1-- (4 chlorophenylthiocarbamyl) 2 (1 pyrrolidylmethyDpiperidine was prepared from 8.4 g. of 2-(1-p'yrrolidylrnethyl)piperidine and 8.5 g. of p-chlorophenylism thiocyanate in 30 ml. of anhydrous ethanol using the procedure described in Example 27. After recrystallizationfrom ethanol there Was obtained 10.5 g. of 1-(4: chlorophenylthiocarbarnyl) -2-(1 pyrrolidylrnethyDpiperidine, M.P. 110-110.6 C. (corn).

Analysis.-Calcd. for C l-I ClN S: Cl, 10.49; N, 12.44. Foundf C1, 1050; N, 12.53.

Example 93 Example 94 i j 1 (4 chlorophenylthiocarbamyl) 2 [2j- (2-diethy1; amino)ethyl]-6-methylpiperidine was prepared from g. of 2-[2-(2-diethylamino)ethyl]-6-methylpiperidine and 8.5 of 4-chlorophenylisothiocyanate in 25 ml; of absolute, ethanol "using the procedure described in Example 27; The 14.5 g. of 1.-(4-chl orophenylthiocarbamyl)-2-[2- (Z-diethylamiho)ethyl1-6-methylpiperidine thus obtained had the M.P. 123-125 C. (corn).

Analysis.Calcd. for C H ClN S: Cl, 9.64; N, 11.42.

Found: Cl, 9.73; N, 11.22.

Example 95- i Kara-1 [2-(4-hydroxyethyl 1 pipetazinyDethyH-j ethylpyridine Wasprepared from 125 g. of 1-(2-hydroxyethyl'l-piperazinejand. 133 g. of S-ethyI-Z-vihylpyridine using the'procedure described above in Example 4(a).

' Aften-histillation in vacuo there. 'was obtained 181 'g. of

2- [2 (4-hydroxyethyl 1 pipera'zinyl)ethyll-S-ethylpyri- IZ-( v r y th r.1+p P a y y1]-5 I ethylpiperidine was prepared by, hydrogenation of 181 g.

"of 2- [2- (4-hydroxyethyl- 1 -piperazinyl) ethyl] -5-ethylpyridine using the procedure described above in. Example 1(a). Distillation gave 84.3 g. of 2-[2-(4-hydroxyethyl- .(corr.).

2 l-piperazinyl) ethy1]-5-ethy1piperidine, B.P. 156-159 C./ 0.08 mm.

Analysis.Calcd. for C H N O: C, 66.86; H, 11.60; N, 15.60. Found: C, 66.85; H, 11.61; N, 15.10.

(c) 1-(4 chlorophenylthiocarbamyl)-5-ethyl-2-[2-(4- hydroxyethyl-l-piperazinyl)ethyl]piperidine was prepared from 13.5 g. of 2-[2-(4-hydroxyethyl 1 piperazinyl)- ethyl]-5-ethylpiperidine and'8.5 g. of p-chlorophenylisQ- thiocyanate in 70 cc. of absolute ethanol using the procedure described in Example 27.- There was thus obtained 4 g. of 1-(4-chlorophenylthiocarbamyl)-5-ethyl- 2- [2-(4 hydroxyethyl 1 piperazinyl)ethy1]piperidine, M.P. 142-146 C. (COIL).

Analysis.Calcd. for C H C1N OS: Cl, 8.08; S, 7.30.

Found: C1, 8.09; S, 6.97.

Example 96 (a) 3-[2 (2 pyridyl)ethyl] 3 azabicyclo[3,2,2]- nonane was prepared from 125 g. of 3-azabicyclo[3,2,2]- nonane and 105 g. of 2-vinylpyridine using the procedure described above in Example 4(a). There was thus obtained 160 g. of 3-[2-(2-pyridyl)ethyl] 3 azabicyclo- [3,2,2]nonane, B.P. 126-127" C./0.2 mm.

Analysis.Ca1cd. for C H N C, 78.21; H, 9.63; N, 12.16. Found: C, 77.94; H, 9.53; N, 12.10.

(b) 3-[2-(2 piperidyDethyl] 3 'tzabicyclo[3,2,2]-

nonane was prepared by hydrogenation of 155 g. of 3- [2-(2-pyridyl) ethyl]-3-azabicyclo[3,2,2]nonane using the procedure described above in Example 1(a). There was thus obtained 37 g. of 3-[2-(2-piperidyl)ethyl] -3-azabicycl[3,2,2]nonane, B.P. 126 C./ 0.7 mm.

Analysis.C-a1cd. for C H N C, 76.21; H, 11.94;

N, 11.87. Found: C, 75.91; H, 11.95; N, 12.16.

(c) 1 carbamy1-2-[2 (3 azabicyc1o[3,2,2]nonyl)- ethyl]piperidine was prepared from 23.6 g. of 3-[2-(2- piperidyl)ethyl] -3-azabicyclo [3,2,2]nonane and 16.2 g. of potassium cyanate using the procedure described above in Example 1(b) Recrystallization from ethyl acetate gave 11.3 g. of.1-carbamy1-2-[2-(3-azabicyclo[3,2,2]nonyl)- ethy1]piperidine, M.P. 121124 C. (corr.).

Analysis.Calcd. for C H N O: C, 68.77; H, 10.46;

N, 15.04. Found: C, 69.00; H, 10.72; N, 15.09.

Example 97 (a) 2-[2-(4-pheny1 1 piperazinyl)ethyl] -5 -ethylpyridine was prepared from 1 16 g. of l-phenylpiperazine and 95 g. of 5-ethyl-2-viny1pyridine using the procedure described in Example 4(a). After recrystallization from ,n-heXane there was obtained 144 g.'of 2-[2-(4 phenyl-1- piperaziny1)ethyl] 5 ethylpyridine, M;P. 75-76 C.

Analysis.Calcd. for C H N C, 77.25; H, 8.53;:N,

14.22. Found: C, 77.33; H, 8.32; N, 14.31.

(b) 2-[2-(4 phenyl 1 piperazinyl)ethylLS-ethylpiperidine was prepared by hydrogenation of 118 g. of 2- [2- (4-phenyl-1-piperazinyl) ethyl] -5ethylpyridine using the procedure described above in Example 1(a). The

zinyl)ethyl]piperidine, M.P. 8791 C. (corn);

57.6 gIof 2-[2-(4-phenyl 1 piperazinyDethyl]-5-ethylpiperidine obtained had the B.P. 182 C./ 0.2 mm.

Analysis.Calcd. for C H N C, 75.69; H, 10.37; N, 13.94. Found: C, 75.48; 1-1, 10.20; N, 13.99.

(c) 1 carbamyl-Z-[2-(4-phenyl-1-piperazinyl)ethyl]- S-ethylpiperidine was prepared from 24 g. of 2-[2-(4- phenyl-l-piperazinyl) ethyl] S-ethylpiperidine and 13 g. of

potassium cyanate using the procedure described in Example 1(b). Recrystallization from methanol gave 3.2 g. of 1 carbamyl-2-[2-(4-phenyl-1-piperaziny1)ethyl]-5- ethylpiperidine, M.P. 187190 C. (com).

Analysis.Calcd. for'C H N Oz C, 69.73; H, 9.36; N, 16.26. Found: C, 70.00; H, 9.63; N, 16.37.

Example 98 (a) 4-[2-(4-pheny1- 1 piperaziny1)ethyl]pyridine was prepared from 116 g. of l-phenylpiperazine and 75 g. of

'heptyl)ethyl]-6-rnethylpiperidine, M.P. 118121 (corr.), by reaction of 2-[2-.( l-azacycloheptyl)ethyl]-6- methylpiperidine with 4-chlorophenylisothiocyanate. The procedures of general applicability discussed 4-vinylpyridine using the procedure described in Example 4(a). There was thus obtained g. of 4-[2-(4-pheny1- l-piperazinyl)-ethyl]pyridine, M.P. 82-86 C. (corr.).

Analysis.-Calcd. for C17H21N3Z C, 76.37; H, 7.92; N, 15.72. Found: C, 76.72; H, 7.63; N, 15.73.

(b) 4-[2-(4-pheny1-1-piperazinyl)ethyl]piperidine was prepared by hydrogenation of 110' g. of 4-[2-(4-phenyl-1- piperazinyl)ethyl] pyridine using the procedure described in Example 1(a). There was thus obtained 54 g. of 4- [2-(4-phenyl 1 piperazinyl)ethyl]piperidine, M.P. 96- 98 C.

'(c) 1 carbamy1-4-[2-(4-pheny1-l-piperazinyl) ethyl]- piperidine was prepared from 20 g. of 4-[2-(4-pheny1-1- piperazinyl)ethyl]piperidine and 11.9. g. of potassium cyanate using the procedure described in Example .1(b). The 1 carbamyl-4-[2-(4-phenyl 1 piperaziny1)ethy1]- piperidine thus obtained had the M.P. 184-187 C. (corn).

'ylisocyanate;

1 (2-chlorophenylcarbamyl)-2- [2-(1-piperidy1)ethyl]- piperidine, M.P. 112-114 C. (corn), by reaction of 2- [2-(1-piperidy1)ethyl]piperidine with 2-chlorophenylisocyanate;

'1 diethylcarbamyl-2-(Z-diethylarninoethyl)-6-methy1- piperidine, B.P. 103 C./0.06 mm, by reaction of 2-(2- diethylarninoethyl) 6 methylpiperidine with diethylcarbamoyl chloride; i

1'-(2 chlorophenylcarbarnyl)-2- [2-(4-phenyl-1-pipera 1 (N,N -dimethylcarbamyl) 2 [2 (4 phenyl 1- piperazinyl)-ethyl]piperidine, M.P., dihydrochloride salt -173.178 C. (corn), by reaction of 2-[2-(4-phenyl-1- piperazinyl)ethyl]piperidine and dirnethylcarbamoyl chlo ride followed by reaction with ethereal hydrogen chloride; 7

. 1 (4-nitrophenylthiocarbamyl)-2-[2-(.1 piperidyl) ethyl]-5-ethylpiperidine, M.P. 192195 C., by reaction of 2- [2-(1-piperidyl)ethy1] 5 ethylpiper-idine; with 4-nitrophenylisothiocyanate; F

1 (3-methylphenylcarbamyl)-2-[2-(4 v-- morpholinyl) ethyl]-piperidine, M.P. 98-101 C. (corn), by reaction of 2-[2-(4-morpholinyl)'ethyl]piperidine with 3-methy1- phenylisocyanate; v

1 (4-chlorophenylthiocarbamyl)-2-[2-(1 -piper-idy1)- ethyl]-6-methylpiperidine, M.P. 124 127" C. (corn), by reaction of 2-[2-(1-piperidy1)ethyl]-6-methylpiperidine with 4-chlorophenylisothiocyanate;

1 (4-chlorophenylthiocarbamyl) 2 [2 (1-pyrro1idy1)- ethyl]e6-methylpiperidine by reaction of 2 -[2-(1-pyrro1- idyl') -ethyl] -6-rnethylp iperidine with 4-ch1orophenylisothiocyanate;

1 (4-chlorophenylthiocarbamyl) 2-[2-(1-azacyc1oabove can be used to prepare the following compounds: 1 (3-trifluorornethylbenzylcarbainyl)-2 [2-(2,6-dimethyl-l-piperidyl)ethyl]piperidine by reaction of 2-[2- (2,6-dimethyl-1-piperidyl)ethyl]piperidine with 3-trifluorornethylbenzylisocyanate.

1 (4 iodophenylthiocarbamyl)-2-[2 1-pyrrolidyl)- ethyl] S-butylpiperidine by reaction of 2-[2-(1-pyrlevel. erties and are effective, for example, against fiagellate pro- 2? rolidyl)-ethyl]--butylpiperidine with 4-iodophenylisothiocyanate.

.1 (Z-methoxybenzylcarbamyl)-2-[3 (1-piperidyl)- PropyHpiperidine by reaction of 2-[3-(1-piperidyl)pro-- pyl]-piperidine with Z-rnethoxybenzylisocyanate.

l diethylcarbamyl 2-[2-(2,5 dimetl1yl-4-morpholinyl)ethyl]piperidine by reaction of 2[2-(2,5-di1nethyl 4-morpholinyl)-ethyl]piperidine with diethylcarbamoyl chloride.

1 (Z-fiuorophenylthiocarbamyl) 3-[6-(l-piperidyl)- hexyl1pipe1idine by reduction of 3-[6-( l-piperidyDhexyl] pyridine obtained by reduction of the amide, N,N-pentamethylene-6-(3-pyridyl)hexanamide prepared by thecondensation of ethyl .6-(3-pyridyl)hexanoate with piper idine.

1 benzylcarbamyl 4-[2-(4-phenyl-1 piperazinyl) ethyl] -6-methylpiperidh1e by reaction of 4-[2-(4-phenyll-piperazinyl)ethyl]-6-methylpiperidine with benzyliso- 'cyanate.

1 (3,4,5 trimethoxyphenylthiocarbamyl) 2-(2-dioxyphenylisothiocyanate with 2 (2-dibutylaminoethyl) piperidine.

The compounds of the invention are valuable thera-' peutic agents for producing a lowering of the blood pressure of mammals and are therefore useful as hypotensive ministered intraveneously in the mouse, have LD s in the range 50-250 mg/kg. The LD is defined as the lethal dose for 50% of the animals at that particular dose The compounds also have chemotherapeutic proptozoa of the genus Trichomonas, and against the nematode worm of the genus Strongylodies.

The compounds of the invention can be formulated for use in the same way as conventional hypotensive agents,

- such'as reserpine preparations, or as conventional'triwherein T is a member of the group consisting ,of di-" rlower-alkylamino, l-pyrrolidyl, C-lower-alkylated-l-pyr- .rolidyl,. l-pipen'dyl, -C-lovver-alkylated-l-piperidyl,

4- morpholinyl, C-lower-alkylated-4-morpholinyl, 4-thiomorphohnyl, l-hexamethyleniminyl, 2-(1,2,3,4-tetrahydroisoquinolyl), l-decahydroquinolyl, 4-phenyl-l-piper- .azinyl, 4-lower-alkyl-l-piperazinyl, 4-(2-hydroxyethyl)-lpiperazinyl, anilino and anilino ring-substituted by from one to three members of the group consisting of loweralkyl. and loWer-alkoxy, A is lower-alkylene having one to sin carbon atoms, X is a member of-the group combutylaininoethyhpiperidine by reaction of 3,4,5-trimethlpipe'razinyl)ethyl]piperidine.

'sisting of oxygen and sulfur, R is a member of the group consisting of hydrogen, lower-alkyl and lower-alkenyl, R

'is a member of the group consisting .of hydrogen, loweralkyl, loWer-alkenyl, phenyl, benzyl and phenyl and ben zyl ring-substituted by from one to three members of the group consisting of loWer-alkyl, lower-alkoxy, nitro, halogen and 'trifiuoromethyl, and W is a member of the group consisting of hydrogen and lower-alkyl. p

2. 1 (4-chlorophenylthiocarbamyl)-2-[2-(1 piperidyl)-ethy1]piperidine.

3. 1 (4 nitrophenylcarbamyl) 4 {2 (1 piperidyl)ethyl] -piperidine.

4. 1 (N,N diethylcarbamyl) 2 2- 4 henyl s 1- 5. 1 (4-chlorophenylthiocarbamyl)-2-(2-diethylami no-ethyl)piperidine.

6. 1 (4-cl1lorophenylthiocarbamyl)-2[2-(4-morpholinyl) ethyl]-5-ethylpiperidine. 1 r 7. l- (2-chlorophenylcarbamyl)2-[2-(2,6'dimethyl-4 morpholinyl ethyl] piperidine.

8. lcarbamyl-2-(2-anilmoethyl)piperidine.

9. l-carbamyli- [2- l-pyrrolidyl) ethyl] piperidine.

l0. 1 (phenylcarbamyD-Z-[Z- (l-pyrrolidyl)ethyl]- piperidine.

11. l (phenylthiccarban1yl)-2-[2-(1 pyrrolidyl)ethyl]- piperidine.

12. 1 l-chlorophenylthiocarbamyl)-2-[2-(l-pyrrolidyl ethyl] pip eridine.

l3. 1- (4-chlorophenylthiocarbamyl)-2-[2-(l-pyrrolidyl)ethyl]-5-ethylpiperidine. V

l4. 1 (2-chlorophenylthiocarbamyl)-2-[2-(l-pyrrol- .idyl ethyl -5-ethylpip eridine.

15. 1-carbamyl-4-{2-(l-pyrrolidyl)ethyHpiperdin.

16. 1 carbamyl-2-[2-( l-hexamethyleniminyl)ethyl]- piperidine.

17. 1 --(4-nitrophenylcarbamyl)-2 [Z-(I-hexamethyleniminyl) ethyl] piperidine 18. 1 (4-chlorophenylthiocarbamyl) 2-[2-(1-hexamethyleniminyl) ethyl] piperidine.

19. l (4-chlorophenylthiocarbamyl) Z-[Z-(I-hexarnethyleniminyDethyl]-5-ethylpiperidine.

20. 1 (3,4-dichlorophenylthiocarbamyl)-2-[2-(1-l1examethyleniminyl)ethylJpiperidine. e

21. 1' (4-chlorobenzylthiocarbamyl) Z-[Z-(I-hexamethyleniminyhethyl]piperidine.

22. 1 (4-nitrophenylcarbamyl) 2-i[2-(4-rnethyl-lpiperazinyl)ethyl]piperidine;v 23. l.- (4,-chlorophenylcarbamyl) 2-[ 2-(4-m ethyl-lr-r I l-piperazinyhethyl]piperidine.

28.,A compound having the structural formula V l 0 ON (lower alkyl) 3 piperidine.

piperidine; V I i No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Non 3, 133,061 May 12 1964 Frederick K Kirchner It is hereby certified that error appears in the above numbered pat ant requiring correction and that the said Letters Patent should read as corrected below.

Column 5 line 36 for "C H CNa" read C H ONa column 8 line l l for "alternation" read alteration column 16 line 14, for is read in line 6O for "136-148 C."

read 186-138 C, lines 70 and 71 for "l(4chloro phenylisocarbamyl)'" read l-( ichlorophenylthiocarbamyl) column 1'1? line l2 for "4-chl0rophenylisocyanate" read 4-chlorophenylisothiocyanatel line 55 for "lallylthio carbambyl" read l-allylthibcarbarmyl column 18 line 25 for "805" read 805 g column 21 line 28, for

"12,7" read 120? go column 22 line 14 for "2[2-l-" read 2[2(l--; lines 50 and 51 for (l-hexamethyleniminyl (ethylJ piperidine read (1-=hexamethyleniminyl) ethyljpiperidine 5 lines 57 and 58,, for "(4methyl'lpiperidyl(ethyl]piperidine" read (4methyl-l-piperidyl) ethyljpiperidine column 23 line 6 for "reported" read prepared column 26 line 7 1 for "[2lpyrrolidyl) read [2-(l-pyrrolidyl) column 27 lines 313- to 31 for "sadation" read sedation column 28 line l3 for "1'(Nc iN" read l(N N line l7 for "2[2 read 2-[2 --c Signed and sealed this Nth day of November 1964,

(SEAL) Attest:

ERNEST We SWIDER EDWARD J, BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOND HAVING THE STRUCTURAL FORMULA 